18-58671684-C-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_006785.4(MALT1):c.41C>G(p.Ser14Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000272 in 1,249,392 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S14L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

MALT1
NM_006785.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.543

Variant links:

Genes affected

MALT1 (HGNC:6819): (MALT1 paracaspase) This gene encodes a caspase-like protease that plays a role in BCL10-induced activation of NF-kappaB. The protein is a component of the CARMA1-BCL10-MALT1 (CBM) signalosome that triggers NF-kappaB signaling and lymphoctye activation following antigen-receptor stimulation. Mutations in this gene result in immunodeficiency 12 (IMD12). This gene has been found to be recurrently rearranged in chromosomal translocations with other genes in mucosa-associated lymphoid tissue lymphomas, including a t(11;18)(q21;q21) translocation with the baculoviral IAP repeat-containing protein 3 (also known as apoptosis inhibitor 2) locus [BIRC3(API2)-MALT1], and a t(14;18)(q32;q21) translocation with the immunoglobulin heavy chain locus (IGH-MALT1). Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, May 2018]

MALT1 links:

MALT1-AS1 (HGNC:55306): (MALT1 antisense RNA 1)

MALT1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11658299).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000112 (17/151954) while in subpopulation AFR AF= 0.000385 (16/41532). AF 95% confidence interval is 0.000241. There are 0 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MALT1	NM_006785.4 linkuse as main transcript	c.41C>G	p.Ser14Trp	missense_variant	1/17	ENST00000649217.2
MALT1-AS1	NR_164150.1 linkuse as main transcript	n.190G>C		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MALT1	ENST00000649217.2 linkuse as main transcript	c.41C>G	p.Ser14Trp	missense_variant	1/17		NM_006785.4	P3	Q9UDY8-1
MALT1-AS1	ENST00000588144.2 linkuse as main transcript	n.194G>C		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

151846

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000155

AC:

AN:

1097438

Hom.:

Cov.:

AF XY:

0.0000152

AC XY:

AN XY:

524882

show subpopulations

Gnomad4 AFR exome

AF:

0.000664

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000460

GnomAD4 genome

AF:

0.000112

AC:

AN:

151954

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74276

show subpopulations

Gnomad4 AFR

AF:

0.000385

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Combined immunodeficiency due to MALT1 deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 19, 2022

This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 14 of the MALT1 protein (p.Ser14Trp). This variant is present in population databases (no rsID available, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with MALT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 848660). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 15, 2023

The c.41C>G (p.S14W) alteration is located in exon 1 (coding exon 1) of the MALT1 gene. This alteration results from a C to G substitution at nucleotide position 41, causing the serine (S) at amino acid position 14 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.64

Cadd

Benign

Dann

Benign

0.94

DEOGEN2

Benign

0.21

T;T;.

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.00070

M_CAP

Uncertain

0.089

MetaRNN

Benign

0.12

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

N;N;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-0.40

N;.;N

REVEL

Benign

0.010

Sift

Benign

0.037

D;.;D

Sift4G

Uncertain

0.032

D;.;D

Polyphen

0.89

P;P;P

Vest4

0.28

MutPred

0.30

Gain of catalytic residue at S14 (P = 0.0032);Gain of catalytic residue at S14 (P = 0.0032);Gain of catalytic residue at S14 (P = 0.0032);

MVP

0.29

MPC

0.86

ClinPred

0.50

GERP RS

0.25

Varity_R

0.033

gMVP

0.56

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over